Recent studies have suggested that circulating tumor DNA (ctDNA) testing has prognostic value in colorectal cancer, but researchers maintain that additional studies are needed to confirm whether and how ctDNA testing should be used in practice.
A study published in Nature Medicine showed that ctDNA testing can identify patients with colorectal cancer who are at high risk of relapse after surgery and can benefit from adjuvant chemotherapy.1
A presentation at the 2023 ASCO Gastrointestinal Cancers Symposium suggested that post-operative ctDNA is “highly prognostic” in colon cancer.2 Another presentation suggested that ctDNA can be useful in patients with oligometastatic colorectal cancer.3 However, both presenters said more research is needed before ctDNA can be used in clinical practice.
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GALAXY Results
In the Nature Medicine article, researchers reported results from GALAXY, an observational arm of the CIRCULATE-Japan study, which was designed to assess ctDNA surveillance after curative-intent surgery for stage II-IV colorectal cancer.1
The researchers performed whole-exome sequencing and analyzed the results to design a tumor-informed, personalized ctDNA assay. A total of 8374 genes were selected for 1039 patients. TP53 (25.6%) and APC (17.5%) were found most frequently, but 55.7% of genes were unique to each patient’s tumor.
At 4 weeks after surgery, 187 patients were ctDNA-positive, and 852 patients were ctDNA-negative. At a median follow-up of 16.74 months, recurrences were seen in 61.4% of patients who were ctDNA-positive at 4 weeks after surgery and 9.5% of patients who were ctDNA-negative (hazard ratio [HR], 10.0; 95% CI, 7.7-14.0; P <.0001).
At 18 months, the disease-free survival (DFS) rate was 38.4% in the ctDNA-positive group and 90.5% in the ctDNA-negative group. This trend was seen regardless of disease stage.
In a multivariate analysis of patients with stage II-III disease, ctDNA positivity at 4 weeks after surgery was the most significant prognostic factor for disease recurrence (HR, 10.82; 95% CI, 7.07-16.6; P <.001).
ctDNA detection was also predictive of benefit from adjuvant chemotherapy. Patients with high-risk stage II-III colorectal cancer who were ctDNA-positive at 4 weeks had a significant benefit from adjuvant chemotherapy (adjusted HR [aHR], 6.59; 95% CI, 3.53-12.3; P <.001).
This trend was seen across all disease stages, including stage II (aHR, 5.84; 95% CI, 1.36-25.1; P =.018), stage III (aHR, 7.02; 95% CI, 3.46-14.2; P <.0001), and stage IV (aHR, 4.0; 95% CI, 1.85-8.8; P <.0001).
Not receiving adjuvant chemotherapy was a negative prognostic factor in ctDNA-positive cases (aHR, 5.03; 95% CI, 3.17-8.0; P <.001). On the other hand, no benefit from adjuvant chemotherapy was seen in ctDNA-negative cases (aHR, 1.71; 95% CI, 0.80-3.7; P =.167).
Data on ctDNA clearance by 6 months after surgery were available for 182 of the 187 patients with ctDNA-positive results at week 4. Approximately half of patients (n=92) received adjuvant chemotherapy, and the other half (n=90) were placed under observation.
ctDNA clearance was higher with adjuvant chemotherapy (68.48%) than with observation (12.2%; aHR, 8.50; 95% CI, 4.2–17.3; P <.0001).
When the researchers evaluated the ctDNA clearance status of minimal residual disease (MRD)-positive patients who were treated with adjuvant chemotherapy, patients without ctDNA clearance had inferior DFS (aHR, 11; 95% CI, 5.2–23.0; P <.0001).
The researchers concluded that postsurgical ctDNA status 4 weeks after surgery for stage II-IV colorectal cancer appears to be more accurate in assessing prognosis for individual patients than the currently used clinicopathologic criteria and is a good predictor of adjuvant chemotherapy benefit. They noted the need to verify their results in additional trials.
